Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects – A review

https://www.cell.com/cell/pdf/S0092-8674(15)00853-3.pdf

An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis

Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.

https://clincancerres.aacrjournals.org/content/clincanres/15/4/1126.full.pdf

Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy.

The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well understood why pyruvate supplementation allows cells lacking ETC function to proliferate. We used a CRISPR-based genetic screen to identify genes whose loss sensitizes human cells to phenformin, a complex I inhibitor. The screen yielded GOT1, the cytosolic aspartate aminotransferase, loss of which kills cells upon ETC inhibition. GOT1 normally consumes aspartate to transfer electrons into mitochondria, but, upon ETC inhibition, it reverses to generate aspartate in the cytosol, which partially compensates for the loss of mitochondrial aspartate synthesis. Pyruvate stimulates aspartate synthesis in a GOT1-dependent fashion, which is required for pyruvate to rescue proliferation of cells with ETC dysfunction. Aspartate supplementation or overexpression of an aspartate transporter allows cells without ETC activity to proliferate. Thus, enabling aspartate synthesis is an essential role of the ETC in cell proliferation.

An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis

Most of the metal ions are carcinogens and lead to serious health concerns by producing free radicals. Hence, fast and accurate detection of metal ions has become a critical issue. Among various metal ions arsenic, cadmium, lead, mercury and chromium are considered to be highly toxic. To detect these metal ions, electrochemical biosensors with interfaces such as microorganisms, enzymes, microspheres, nanomaterials like gold, silver nanoparticles, CNTs, and metal oxides have been developed. Among these, nanomaterials are considered to be most promising, owing to their strong adsorption, fast electron transfer kinetics, and biocompatibility, which are very apt for biosensing applications. The coupling of electrochemical techniques with nanomaterials has enhanced the sensitivity, limit of detection, and robustness of the sensors. In this review, toxicity mechanisms of various metal ions and their relationship towards the induction of oxidative stress have been summarized. Also, electrochemical biosensors employed in the detection of metal ions with various interfaces have been highlighted.

A review on detection of heavy metal ions in water – An electrochemical approach

Gallic acid inhibits the growth of HeLa cervical cancer cells via apoptosis and/or necrosis.

MG132 (carbobenzoxy-Leu-Leu-leucinal) is a peptide aldehyde, which effectively blocks the proteolytic activity of the 26S proteasome complex. We evaluated the effects of MG132 on the growth of human cervix cancer HeLa cells in relation to the cell growth, reactive oxygen species (ROS) and glutathione (GSH) levels. Dose-dependent inhibition of cell growth was observed in HeLa cells with an IC50 of approximately 5 microM MG132 for 24 h. DNA flow cytometric analysis indicated that treatment with MG132 induced S, G2-M or non-specific phase arrests of the cell cycle dose-dependently. Treatment with MG132 induced apoptosis in a dose-dependent manner, as evidenced by sub-G1 cells and annexin V staining cells. Treatment with MG132 also induced the loss of mitochondrial membrane potential in HeLa cells. The intracellular ROS levels including O2*- were significantly increased in MG132-treated cells. Furthermore, the depletion of intracellular GSH content was observed in cells treated with MG132. In conclusion, MG132 inhibited the growth of HeLa cells via inducing the cell cycle arrest as well as triggering apoptosis. The changes of ROS and GSH by MG132 were closely related to apoptosis in HeLa cells.

/pdf/the-effect-of-mg132-a-proteasome-inhibitor-on-hela-cells-in-56jl0qz09y.pdf

The effect of MG132, a proteasome inhibitor on HeLa cells in relation to cell growth, reactive oxygen species and GSH.

Gallic acid-induced lung cancer cell death is related to glutathione depletion as well as reactive oxygen species increase.

Antimycin A (AMA), an inhibitor of electron transport in mitochondria, has been used as a reactive oxygen species (ROS) generator in biological systems. Here, we investigated the in vitro effect of AMA on apoptosis in HeLa cells. AMA inhibited the growth of HeLa cells with an IC(50) of about 50 microM. AMA efficiently induced apoptosis, as evidenced by flow cytometric detection of sub-G1 DNA content, annexin V binding assay, and DAPI staining. This apoptotic process was accompanied by the loss of mitochondrial membrane potential (DeltaPsi(m)), Bcl-2 down-regulation, Bax up-regulation, and PARP degradation. All caspase inhibitors used in this experiment, especially pan-caspase inhibitor (Z-VAD), could rescue some HeLa cells from AMA-induced cell death. When we examined the changes of the ROS, H(2)O(2) or O(2) (.-), in AMA-treated cells, H(2)O(2) and O(2) (.-) were markedly increased. In addition, we detected the depletion of GSH content in AMA-treated cells. Pan-caspase inhibitor showing the efficient anti-apoptotic effect significantly reduced GSH depletion by AMA. Superoxide dismutase (SOD) and catalase did not reduce intracellular ROS, but these could strongly rescue the cells from apoptosis. However, these anti-apoptotic effects were not accompanied by the recovery of GSH depletion. Interestingly, catalase significantly decreased the CMF negative (GSH depletion) and propidium iodide (PI) positive cells, indicating that catalase strongly maintained the integrity of the cell membrane in CMF negative cells. Taken together, these results demonstrate that AMA potently generates ROS, induces the depletion of GSH content in HeLa cells, and strongly inhibits the growth of HeLa cells throughout apoptosis.

An ROS generator, antimycin A, inhibits the growth of HeLa cells via apoptosis.

We investigated the in vitro effects of arsenic trioxide on cell growth, cell cycle regulation, and apoptosis in As4.1 juxtaglomerular cells. Arsenic trioxide inhibited the growth of As4.1 cells wi...

Woo Hyun Park

Papers

Gallic acid inhibits the growth of HeLa cervical cancer cells via apoptosis and/or necrosis.

The effect of MG132, a proteasome inhibitor on HeLa cells in relation to cell growth, reactive oxygen species and GSH.

Gallic acid-induced lung cancer cell death is related to glutathione depletion as well as reactive oxygen species increase.

An ROS generator, antimycin A, inhibits the growth of HeLa cells via apoptosis.

Arsenic trioxide inhibits growth of As4.1 juxtaglomerular cells via cell cycle arrest and caspase-independent apoptosis